RESUMO
PURPOSE: Hetrombopag, a novel, oral small molecule thrombopoietin receptor agonist, exhibits an obvious thrombocytopoietic effect with good safety. Hetrombopag is currently under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). The objectives of this study were to assess the effect of high-fat and high-calorie food on the pharmacokinetic and pharmacodynamic (PK/PD) profiles of hetrombopag in healthy volunteers. METHODS: An independent, single-dose, open-label, randomized-sequence, crossover trial was conducted. Healthy volunteers received hetrombopag 7.5-mg tablets in the fasted state or with a high-fat, high-calorie breakfast. The effects of the high-fat and high-calorie food on the PK/PD profiles of hetrombopag were evaluated by using a noncompartmental analysis and a semi-physiological model. FINDINGS: Twelve Chinese healthy volunteers were enrolled. Mean plasma AUC0-t and Cmax decreased by 98.7% and 95.0%, respectively, when hetrombopag was administered with high-fat and high-calorie food. The semi-physiological PK/PD model analysis showed that the absorption rate constant at the first absorption site was almost halved at the fed condition. The change in platelet counts in the fed condition was not sufficiently as sensitive as that in the fasted condition. IMPLICATIONS: High-fat and high-calorie food were associated with significantly reduced systemic exposure and platelet count sensitivity. Thus, hetrombopag should be taken in a fasted state to avoid the impact of food on bioavailability and platelet counts. ClinicalTrials.gov identifier: NCT02409394.